Phase II Trial of Intermittent Therapy in Patients with Metastatic Renal Cell Carcinoma Treated with Front-line Ipilimumab and Nivolumab.

The combination of ipilimumab/nivolumab is approved for patients with treatment-naïve, intermediate-, and poor-risk metastatic renal cell carcinoma (mRCC), but duration of therapy and safety/efficacy of reinduction at progression is unknown. A phase II trial of intermittent ipilimumab/nivolumab with reinduction at progression was conducted (NCT03126331). Patients with treatment-naïve mRCC were treated with induction ipilimumab/nivolumab followed by up to 24 weeks of maintenance nivolumab. Patients who achieved a complete response (CR) or partial response (PR) were eligible for inclusion and entered a treatment-free observation period. Patients were restaged every 12 weeks. Patients with no disease progression (PD) remained off therapy. Upon PD, patients were re-challenged with 2 doses of ipilimumab/nivolumab every 3 weeks. Study objectives were to estimate success rate of observation in patients who achieve a CR/PR, and to assess toxicity in patients undergoing reinduction. The study accrued slower than expected and was closed prior to the anticipated accrual goal of 20 patients. Nine patients were included; 89% male, median age 57, 67% clear-cell histology, and 78% intermediate-risk by IMDC criteria. Response to ipilimumab/nivolumab followed by nivolumab maintenance prior to enrollment was 33% CR and 67% PR. Most (78%) patients have remained off therapy, with a median treatment-free interval (TFI) of 34.3 months (range, 8.7-41.8). Two patients had PD off therapy and received 2 cycles of reinduction ipilimumab and nivolumab. No grade 3 or greater toxicities occurred with reinduction. Both patients developed PD at their first scans after reinduction. This prospective study demonstrates that patients with a radiographic response to ipilimumab/nivolumab can have prolonged treatment-free intervals. Further studies of de-escalation strategies are warranted. NCT03126331 [Date of registration 4/27/2017; https://clinicaltrials.gov/ct2/show/NCT03126331].

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Disclosure MCO has served in consulting or advisory roles for Eisai, Exelixis, Pfizer, Aveo, Merck, and Bristol Myers Squibb; served on speakers bureaus for Bristol Myers Squibb and Merck; received institutional research funding from Bristol Myers Squibb, Pfizer, Merck, Astra-Zeneca, Astellas, Aravive, and Surface Oncology; has received reimbursement for travel and accommodations expenses from Bristol Myers Squibb, Pfizer, Eisai, and Exelixis. AB receives consulting fees from EMD-Serono, Bristol Myers Squibb, Eisai; honoraria from Eisai, Natera, Aveo Pharmaceuticals; research support from Natera, Aveo, Merck, Pfizer, Rubius Therapeutics, Roche, BMS. KEB receives research funding to the institution for preclinical research from Aravive, Arsenal, BMS-LCFA-IASLC, and Pionyr; and has received consulting fees from Alpine Bioscience, Aravive, Aveo, Astrazeneca, BMS, Exelixis, Eisai, Merck, Nimbus, Seagen, Sanofi. AM receives consulting fees from AVEO; honoraria from Integrity CME, Targeted Oncology, Cleveland Clinic, Aptitude Health. SG Reports fees for consulting from Merck, BMS, Gilead, Seattle Genetics, EMD Sorono, Bayer, Foundation Medicine, Astellas; speaker's bureau fees from Gilead, Seattle Genetics, BMS; research funding to institution from Merck, Roche, Novartis, Pfizer, QED, Seattle Genetics, Acrivion, EMD Sorono, Exelixis; owns stock in BionTech, Moderna, Nektar Therapeutics. BIR declares institutional funding from Exelixis, AVEO, Genentech, BMS, Arcus, Merck, Dragonfly Therapeutics, HiberCell, Incyte, Stata Oncology, ADC Therapeutics, Dracen Pharmaceuticals, Janssen, Adela, AstraZeneca, Pionyr, Tempus, VasGene Therapeutics, Gilead, POINT Biopharma, Pfizer, Daiichi Sankyo, Arrowhead Pharmaceuticals, Exelixis, Surface Oncology, and Aravive; has received consulting fees from BMS, Genentech, AVEO and Exelixis, Pfizer, Synthorx, Merck, Corvus, Surface Oncology, Aravive, Alkermes, Arrowhead, Eisai, Nikang Therapeutics, EUSA, Athenex, Debiopharm, and HiberCell.